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Campath (#2)

Posted by Frederick Wasti
Jan 18 2013

I have already mentioned in a previous post, "Campath (#1)" from 12/13/2012, that Campath (Alemtuzumab) was first synthesized in 1979 by Herman Waldemann at Cambridge University in England. However, since then Campath has followed a rather circuitous path for its development and marketing, and it continues to do so, as I will try to demonstrate here in this post.

Nowadays, almost all drug development occurs in the laboratories of large pharmaceutical companies (or in the labs of smaller pharma companies that end up being acquired and absorbed into larger companies). Such was not the case circa 1980, especially in the UK, where many medical discoveries occurred in academic research labs.

The original funding for Campath development came from the UK's Medical Research Council (MRC). The MRC assigned the rights to Campath to the National Research and Development Council (NRDC), which originally had the purpose of coordinating research between academic labs and industry, but which morphed into an industry-leaning organization, renaming itself as the British Technology Group (BTG) in the process, which did not allow Campath (and similar monoclonal antibodies) to be patented by the original developers. Instead, BTG (which had now morphed further into an international pharmaceuticals company in its own right) assigned the rights to Campath to Wellcome Biotech in 1985.

Wellcome later, in 1995, merged with Glaxo Pharmaceuticals to form Glaxo-Wellcome. However, Glaxo-Wellcome, right in the middle of a series of clinical trials, made the business decision to abandon Campath development (apparently having decided that Campath would not ultimately generate enough profit to make it worthwhile). So, in 1997, BTG re-assigned the rights to Campath to a smaller company, LeukoSite Inc., which ended up merging into Millennium Pharmaceuticals in 1999, which continued the necessary clinical trials, and, in 2000, Millennium was able to file a "Biologics Licensing Application" with the US Food and Drug Administration for the use of Campath as an anti-CLL drug.

On May 8th, 2001, Millennium Pharmaceuticals proudly announced in a press release that "The U.S. Food and Drug Administration (FDA) today cleared Campath (Alemtuzumab) humanized monoclonal antibody for marketing as a treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL) who have been treated with alkylating agents and have failed fludarabine therapy".

During the application process, Millennium partnered with ILEX Oncology to complete the development and to obtain final USDA approval, and it ended up that Millennium transferred the development and marketing of Campath to ILEX, and the BTG license to Campath was then also transferred to ILEX. (And your head is probably spinning as much as mine is over all of these business and government machinations, but they're not over yet...)

In 2004, ILEX was acquired by Genzyme Inc., and the marketing of Campath was handed off to Berlex Laboratories in the US, and to Schering AG in Europe (where Campath is branded as MabCampath - the "Mab", of course, referring to "monoclonal antibody"). (Interestingly, before World War II, Berlex and Schering were actually part of the same company, but the US government required that it split into separate US and German companies in 1942.) Meanwhile, in 2006, Berlex became Bayer Pharmaceuticals, which then acquired Schering (which had become an international competitor of Berlex), whereupon Bayer Pharmaceuticals was renamed as Bayer HealthCare Pharmaceuticals. (<Whew!>)

In 2009, Genzyme Corporation entered into an agreement with Bayer to acquire the worldwide rights to Campath, giving Genzyme the primary responsibility for the development and commercialization of Campath as a treatment for CLL and as a treatment for Multiple Sclerosis (MS). Under the agreement, Bayer would continue to fund a portion of Campath's development for MS and would retain an option to co-promote the product for MS treatment upon approval, and would retain the right to develop and commercialize Campath for its use in solid organ transplants. Note that Genzyme thus had a stake in the development and marketing of Campath for both CLL and for MS (even though its approval for use in MS had not yet been given, either in Europe or in the US).

In 2011, Sanofi S.A. (a French multinational pharmaceutical company headquartered in Paris, and the world's fourth-largest in prescription sales) acquired Genzyme, including all of the rights to Campath. Considerable negotiating went on between Sanofi and Genzyme over the ultimate financial worth of Campath - while Sanofi downplayed the extent of its future value as an anti-CLL drug, Genzyme countered by emphasizing its likely much greater financial value as a future drug to be used against MS. As a result, the $20B agreement in which Sanofi acquired Genzyme included provisions for future payments to Genzyme stockholders if Campath did eventually do well as an MS drug. Furthermore, Genzyme was to continue as a division of Sanofi.

Here is where the significance of Campath as a drug that is useful for treating CLL (especially for CLL patients resistant to "regular" CLL drugs, either because they have had repeated treatments already, or because they are 17p-deleted), but which is also useful for treating MS (especially for MS patients in the "Relapsing/Remitting" phase, which is the stage of MS which most MS patients are in when they are first diagnosed), arises. The big problem (from a CLL patient's perspective) is that there is ~much~ more money to be made in the considerably larger MS market, and (as we shall shortly see) this is especially true if Campath is no longer made available to CLL doctors and patients.

I first became aware of the danger to CLL patients needing Campath when, in August, I read in "Dr. Sharman's CLL and Lymphoma Blog" (Dr. Jeff Sharman is a hematologist/oncologist from Oregon) that he "was quite surprised today [8/22/2013] to hear that Campath is being withdrawn from the oncology marketplace". Dr. Sharman pointed out the value of Campath, even though it is never used by the vast majority of CLL patients: "Campath is a 'bit player' in the management of CLL/NHL, but for docs comfortable using it - it can be quite handy. It is one of the few drugs that clearly works in the group of patients with 17p deletion and can be effective when other drugs have failed." Furthermore, "Although it was never much more than 5% of CLL patients [that were] ever treated with the drug - for that 5% it was quite good."

I then also read in "CLL Topics" (a blog by Chaya Venkat),

"Campath is no longer available as a commercial drug to treat CLL patients. What caused this massive change of heart on the part of the drug company that owns this monoclonal? Simple. Money. Lots of it. You see, the very thing that made Campath so immune suppressive in CLL patients – its well documented ability to kill off T-cells and keep T-cell counts low for a long time thereafter – proved to be useful in treating multiple sclerosis. MS is an autoimmune disease, caused by T-cells gone berserk and attacking the myelin sheath of nerves. For these patients, reduced T-cell counts is a blessing, since it gets them much desired remission."

The above results from a two-part problem. First, there is much more money to be made by the selling of Alemtuzumab (to be branded as Lemtrada) to the larger MS market than by the selling of the drug (branded as Campath) to the smaller CLL market. Second (and this may sound strange), it would actually hurt profits by continuing to sell Alemtuzumab as both Campath and as Lemtrada, as compared to selling it as Lemtrada alone. Let me try to explain:

Sanofi just recorded an annual sales figure of $76M from Campath. However, if it receives approval to start selling Lemtrada in 2013, it expects to be able to ramp up to an annual sales volume of between $330M and $400M by 2016. Now that's a significant jump in sales.

But, it's more complicated than just sales alone:

Campath is provided as a 30mg dose, and a typical CLL patient might require three doses per week over a period of several months, at an annual cost of about $60,000. However, an MS patient requires only 12mg per dose, and needs just five doses at the start of the first year of treatment and then only three doses on the anniversary of those first five doses. If Campath is purchased by doctors in 30mg doses, and is then re-formulated into 12mg doses, those doctors can provide it to MS patients for a total cost of about $7,000, which is considerably less expensive than the typical $30,000 cost of other MS drugs. While it is apparently not too common for MS doctors to do this in the US, it is quite commonly done in Europe, even though Alemtuzumab has still not been approved for use in treating MS anywhere in the world.

Obviously, this presents a financial dilemma for Sanofi. It really does not wish to continue tolerating the "off-label" use of Campath for MS treatment, and it is also expected that it would likely choose to raise the ultimate cost of Lemtrada closer to the current cost of about $30,000 for its MS competitors, certainly pricing it considerably above the $7,000 "off-label" cost of Campath for use with MS. What to do? Why, discontinue the sale of Campath. And that's exactly what happened as of September 4th, 2012 - no more Campath to be sold for CLL treatment.

Obviously, both the CLL community and the MS community had concerns. Three of the UK doctors involved in using Campath for treating MS stated in a letter to the editor of the newspaper The Independent,

"The decision has 'serious implications for vulnerable UK patients with MS', because patients who have already started treatment with Campath will 'not be able to get their vital second course'. Meanwhile, newly diagnosed patients may 'miss their window of therapeutic opportunity' to start treatment, putting them at risk of 'progressive, severe disability'. The maneuver established an 'inappropriate precedent', and 'shows little regard for patients whose opportunity to alter the course of their disease is time-limited, and may represent an over-enthusiastic attempt by the parent company to profit from the current situation'."

One of these doctors was further quoted as saying,

"Many of us think it is the best drug for patients with aggressive MS in the early stages of the disease. It's the greedy behavior of the drug company that upsets me. They are just trying to rebrand it and put the price up. It is morally corrupt."

The head of biomedical research at the Multiple Sclerosis Society in the UK said of Alemtuzumab (which, remember, has not yet received official approval for use with MS, either in Europe or in the US):

"The drug 'shows real promise as a potentially new medicine for many people with relapsing-remitting MS. There is no good reason why people with MS who have been allowed to benefit from the treatment should now be denied it. Genzyme needs to come up with a scheme, quickly, that makes their product available to all those people currently being treated and, if it's licensed, price the drug reasonably so it is deemed cost effective' for the UK's National Health Service."

At first, the CLL community was also concerned. Chaya Venkat's description of the CLL aspect was none too subtle:

"Why not market Campath both for CLL and MS? Aha. That is the ~billion~ dollar question. You see, MS patients need very small amounts of Campath. If it is marketed at the present price Campath commands to treat CLL, the company would be selling the drug to MS patients at a significantly cheaper price than other MS therapies. Oy vey! If the drug was available in the marketplace at the present price it gets for CLL, doctors and patients would be buying it at that price, even if they were actually going to use it for treating MS. What to do? Stop selling Campath to CLL patients! Genius! Now the company can jack up the price several times over, sell it only to the MS patient community. I wonder how much they pay the guy who came up with this idea. And how he sleeps at night."

However, Dr. Sharman's blog entry did cautiously offer some potentially good news: "It sounds like there may be patient access programs for patients with CLL - hopefully those materialize. Rumor has it that it may even be given away for free to patients with CLL - obviously that would be a good thing - but I will believe it when I see it. Furthermore, additional barriers may just make a hard to use drug even harder to get."

Chaya Venkat also did offer some guarded optimism (for CLL patients, such as myself, who use Campath):

"In an attempt to avoid scathing public opinion, the company says they will give away Campath free of charge to CLL patients in this country. However, doctors cannot prescribe it in the usual manner, hospital pharmacies cannot supply it, physicians have to call a special phone number, and the physician has to go through a lot of hoops and hassles to justify why a given patient needs Campath. [...] How long will the company continue the compassionate use program? No one knows. Is this only for USA patients? How about CLL patients elsewhere? I do not know."

As it turns out, Genzyme USA (a division of Sanofi) has this current statement online for its "US Campath Distribution Program": "The Campath Distribution Program was developed to ensure continued access to Campath (Alemtuzumab) for appropriate patients. Effective September 4, 2012 Campath will no longer be available commercially, but will be provided through the Campath Distribution Program free of charge. In order to receive Campath, the healthcare provider is required to document and comply with certain requirements."

In an August 9th letter to health care providers, Genzyme made it clear that it would stop selling Campath, not "for any reasons related to product safety, efficacy, or supply, but as part of the company's plan for bringing Alemtuzumab forward as a treatment for a new indication". The company added that it "will continue manufacturing sufficient quantities of Alemtuzumab to supply this patient access program".

And, the good news, for CLL patients that benefit from Campath, is that the "Campath Distribution Program" does seem to be running smoothly. According to Hildy Dillon, the Senior Vice President for Patient Services at the Leukemia and Lymphoma Society,

"There is an extensive patient-distribution system which they have shared with us. They've actually been quite supportive to us and our constituents by telling us what the distribution is and how they have communicated their plans to health care providers who treat our patients - hematology oncologists both in the community and in the major cancer centers. [These doctors] are now aware of how they can access the drug since they no longer will be purchasing it, but they can contact the company directly to get whatever supply they need. Genzyme was in touch with advocacy groups like ours to make sure we were aware of the change and how physicians will be accessing the drug. They've done a lot in their due diligence to inform both the physician community and the patients. It's our understanding that there won't be any shortage of supply and that the patients who need Campath will be able to get it."

Furthermore, Ms. Dillon said that the Leukemia and Lymphoma Society had been assured that Campath would be available for ~all~ patients who need it, including those who may be prescribed it for the first time, even after it is no longer available commercially.

This is hardly the first time that a drug has been re-branded for use with a different purpose. As one example, the drug Sildenafil was originally tested as a treatment for hypertension and angina, but men being treated with it had "side effects" that caused Pfizer to re-purpose the drug - branded as ~Viagra~ - for something else altogether (<grin>).

However, marketing a drug for two different markets at two different prices can have disastrous effects, at least from a public relations perspective. One good example of this is provided by Genentech, with its drugs Lucentis (Ranibizumab) and Avastin (Becavizumab) (both derived from the same parent molecule). Both drugs had showed potential in clinical trials for the treatment of age-related macular degeneration of the eye (AMD), but Genentech never applied for approval for Avastin for use with AMD because it would undercut the Lucentis market for AMD, since Lucentis sells for about $2,000 per injection, while Avastin, approved for and marketed as an anti-cancer drug, costs only $50 per injection. As one article stated, "Genentech has gone to lengths to prevent AMD patients - who go blind if not treated - from getting their hands on Avastin, and everyone agrees that Genentech's position is an example of the corporate rapaciousness that brings the drug industry into bad repute". However, in another article, a spokesman for Sanofi/Genzyme denied the similarity between the two business cases, saying, "We believe the situation that we are managing with Alemtuzumab is unique".

Well, the bottom line for me, however, despite all of the above "sturm und drang", is that Dana-Farber is still able to easily obtain Campath, so that I am still able to receive it (at least as long as I can tolerate it). Still, it is difficult not to be cynical about the situation. As Chaya Venkat has said, "Pity of it is that, while Campath was hardly the wonder drug its supporters claimed it was a few years ago, it was nevertheless an important drug for CLL patients. It was one of few options for patients with the dreaded 17p deletion. If you were not cynical about drug company agendas before, this story might be enough to push you over the edge."

Categories: Leukemia